NZ247037A

NZ247037A - Tetrahydropyrimidine derivatives, preparation, and use as pharmaceutical compositions

Info

Publication number: NZ247037A
Application number: NZ247037A
Authority: NZ
Inventors: Ralf Plate
Original assignee: Akzo Nv
Priority date: 1992-03-04
Filing date: 1993-03-02
Publication date: 1995-10-26
Also published as: NO930776D0; FI930934A0; AU661107B2; FI930934L; MX9301178A; EP0559279A1; AU3393293A; KR930019640A; NO930776L; US5470856A; CA2090170A1; JPH05339245A; ZA931109B

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £47037 24 7 0 3 7 Priority Dato(s): Complete Specification Filed: Class: Publication Date: P.O. Journal No: '26 0CI.1995. iiri, Patents Form No. 5 -2 MAR 1995 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION TETRAHYDROPYRIMIDINE DERIVATIVES WE, AKZO N.V., a Dutch company of Velperweg 76, 6824 Bm Arnhem, THE NETHERLANDS t, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - 1 - (followed by page la) Iq- 24 7.0^7 I bi.l. P.y; -1/f C f OF^ iuE 27 JUN1995 TETRAHYDROPYRIMIDINE DERIVATIVES RgC.ffVED The invention relates to tetrahydropyrimidine derivatives, a process for the preparation thereof, a pharmaceutical composition containing the same, as well as to the use of these tetrahydropyrimidine derivatives for the preparation of a medicament. Related compounds, i.e. 4-piperidinone oxime derivatives, are described in European patent application 445,731. The muscarinic agonist potency of the present compounds is, however, considerably higher than the potency of the known 4-piperidinone oxime derivatives, especially with respect to the important Ml and M3 muscarinic subtypes. The present invention relates to a tetrahydropyrimidine derivative having formula I wherein R^ is hydrogen; R2 is hydrogen, a lower alkyl group, or lower acyl; or R^ and R2 represent together a bond; R2 is hydrogen, COR^ or a lower hydrocarbon group optionally substituted with halogen, CN or aryl; R4 is hydrogen, a lower alk(en)yl group, or aryl (as herein defined; R5 is hydrogen, amino, lower alkyl substituted amino, or a lower alkyl group; Rg is hydrogen or methyl, provided that when R^ and Rj together represent a bond and R^, and R,. are hydrogen, Rg is methyl; and I ( (followed by page 2) R7 is amino, lower alkyl substituted amino, or a lower alkyl group; or a pharmaceutical^ acceptable salt thereof. The compounds of this invention have muscarinic properties. They bind to muscarinic agonist receptor sites with a 2 to 750 fold preference as compared to muscarinic antagonist receptor sites, as is exemplified in their ability to bind preferentially to the agonist site of muscarinic receptors in membrane preparations of rat cerebral cortex, or membrane from rat forebrain. Preferred compounds show an agonist/antagonist binding ratio of between 10 and 400. The tetrahydropyrimidine derivatives are suitable for the treatment of cognition disorders, like presenile and senile dementia, including Alzheimer's disease, learning and memory disturbances, and for the treatment of other cholinergic deficiencies, like Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, and Tourette syndrome or similar conditions characterized by a decrease in cerebral acetylcholine production or release. The compounds of the invention are useful for the treatment of glaucoma and as analgetic agents for the treatment of pain in mammals, including man. Preferred compounds according to the invention are the tetrahydropyrimidine derivative of formula I, in which and R2 represent together a bond, and R3 is a (1-3 C) hydrocarbon group, and more preferably methyl, ethyl, or 2-propynyl, and R5 and R6 are hydrogen, or a pharma-ceutically acceptable salt thereof. The term lower acyl means an acyl group derived from an aliphatic carboxylic acid having 2-6 carbon atoms, like acetyl, propanoyl, or butanoyl. 24 MOV 1894 247 3 10 15 20 25 30 The term lower hydrocarbon group means a branched or unbratiJhed, cyclic or acyclic, saturated or unsaturated aliphatic hydrocarbon group having 1-18 carbon atoms. More preferred are hydrocarbon groups having 1-12 carbon atoms. Examples are methyl, ethyl, propyl, sec-butyl, vinyl, 2-propenyl, ethynyl, 2-propynyl, 2-butynyl, 3-methyl-2-penten-4-ynyl, 3-hex-ynyl, nona-2,5,8-triynyl, cyclopentyl, and cyclohexyl. Preferred are hydrocarbon groups having 1-3 carbon atoms, and more preferred the unbranched hydrocarbon groups having 1-3 carbon atoms. Most preferred are the methyl, ethyl, 2-propenyl, and 2-propynyl groups. The term halogen means F, CI, Br or I. When halogen is a substituent at a lower hydrocarbon group, Cl and F are preferred, F being most preferred. The term lower alkyl means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, isobutyl, propyl, ethyl, and, preferably, methyl. The term lower alk(en)yl means a lower alkyl group as previously defined or a lower alkenyl group having 1-6 carbon atoms, like 2-propenyl, vinyl, 2-butenyl, 1,3-butadienyl, or 2-methyl-l-propenyl. The term aryl means a phenyl group which may be substituted with OH, F, Cl, Br, CF3, CN, lower alkyl, and/or lower alkoxy. The term lower alkoxy means an alkoxy group derived from a lower alkyl group as previously defined. The novel compounds of formula I may be isolated from the reaction mixture in the form of a pharmaceutical ly acceptable salt. The pharmaceutically acceptable salts may treating the free base of 4 24 7 0 formula I with an organic or inorganic acid such as HC1, HBr / HI, H2S04, H3P04, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methane-sulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid. The compounds of this invention may possess a chiral carbon atom, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, among which the racemic mixture. Methods for obtaining the pure enantiomers are well known in the art, e.g. synthesis from chirally pure 3-azabicyclo-alkanol or crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns. Preferred compounds according to this invention have formula I, in which and R2 represent together a bond, and R3 is a (1-3 C) hydrocarbon group. More preferred are those compounds in which R3 is ethyl or 2-propynyl and R4, R5, and R6 are hydrogen, or a pharmaceutically acceptable salt thereof. •» The tetrahydropyrimidine derivatives of the invention can be prepared by methods known for the preparation of analogous compounds. A suitable method is the condensation of an amine having the formula NH2OR3, in which R3 has the previously given meaning, with a 1,6-dihydro-5(4H)-pyrimidinone having the formula II, in which R4, R5, and R6 have the previously given meanings. II 4 247037 formula I with an organic or inorganic acid such as HC1, HBr, HI, H2S04# h3po4, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methane-sulphonic acid, fumaric acid, succinic acid, tartaric 5 acid, citric acid, benzoic acid, and ascorbic acid. The compounds of this invention may possess a chiral ^ carbon atom, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, among which 10 the racemic mixture. Methods for obtaining the pure enantiomers are well known in the art, e.g. synthesis from chirally pure 3-azabicyclo-alkanol or crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography 15 using chiral columns. Preferred compounds according to this invention have formula I, in which Rj and R2 represent together a bond, and R3 is a (1-3 C) hydrocarbon group. More preferred 20 are those compounds in which R3 is ethyl or 2-propynyl and R4, R5, and R6 are hydrogen, or a pharmaceutically 0 acceptable salt thereof. The tetrahydropyrimidine derivatives of the invention 25 can be prepared by methods known for the preparation of analogous compounds. A suitable method is the condensation of an amine having the formula NH2OR3, in which R3 has the previously.given 30 meaning, with a l,6-dihydro-5(4H)-pyrimidinone having the formula II, in which R4, R5, and R6 have the previously given meanings, R4 & 35 JL! J 11 V 1 R6 5 247037 The unsaturated bond of the condensation product may be saturated by methods known for the saturation of imides (particularly when ^ is hydrogen), like borohydride (preferably trimethylamine borohydride) reductions, after which the hydrogen atom attached to the nitrogen atom may optionally be substituted by a group R2, by methods commonly in use for the alkylation or acylation of nitrogen atoms. A suitable method is the acylation with R2'COHal, in which Hal is a halogen atom like 10 chlorine, and R2'CO is R2 when its meaning is lower acyl. Compounds of formula I in which Rj^ and R2 are not together a bond, can also be prepared by condensation of 15 an amine NHR2OR3, in which R2 and R3 have the previously given meanings, and a compound having formula III 20 JL! J ill , in which L denotes a leaving group like a halide, such 25 as chlorine, bromine, or fluorine, or a sulfonyloxy group, such.as tosyl- or mesyloxy, and Rlf R4, R5> and R6 have the previously given meanings. Compounds of formula III may be. obtained from 1,6-dihydro-5(4H)-pyrimidinone having formula II, by 30 reduction of the keto group into a hydroxy group, using standard methods well known to the skilled organic chemist, or by a Grignard-type reaction introducing simultaneously the group Rj^, followed by conversion of the hydroxy group of the thus obtained 5-35 tetrahydropyrimidinol derivatives into a leaving group by customary methods, such as reaction with thionyl- 6 24 70 chloride, phosphorous tribromide, tosylchloride, and the like. Another method for the preparation of compounds of formula I in which and R2 together are a bond, is the condensation of an oxime having formula IV k6hh wherein R3, R4, and R6 have the previously given meanings with an orthoformate derivative having the defined meaning and Alkyl is an alkyl group as previously defined for lower alkyl, and peferably methyl. The compounds of the invention may be administered enterally or parenterally, and for humans preferably in a daily dosage of 0,001-10 mg pep- kg body weight. Mixed with pharmaceutically suitable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing company, 1990, see especially Part 8: pharmaceutical Preparations and Their Manufacture), the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically suitable liquids the compounds can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray. A further application of the compounds of the invention is in the manufacture of ophthalmic preparations, which include solutions, suspensions, ointments and solid dosage forms. For making dosage units, e.g. tablets, the IV formula (Alkyl-0)3C-R5, wherein R5 has the previously 7 247037 use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutical acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. The invention is further illustrated by the following examples. Example 1 1.6-Dihvdro-5(4H ^-pyrimidinone O-methvloxime monohvdrochlor ide 1,3-Diaminoacetone dihydrochloride monohydrate (2.61 g, 14.6 mmol) was dissolved in refluxing methanol. To this solution o-methylhydroxylamine hydrochloride (2.43 ga 29.2 mmol) was added. After reflyxing for 48 hours the solvents were evaporated. The crude product was dissolved in methanol and an excess of trimethylortho-formate was added to the reaction mixture which was heated to reflux. After 24 hours the solvent was removed % in vacuo. Crystallisation from methanol/ethyl acetate afforded 850 mg (36%) of a light-brown crystalline material. Mp. 170.7 °C. Example 2 1,6-Dihyflr<?-5 (4H) -pyrimlflinone Q-ethyloxime nwnQhydrpchlpri<te 8 247037 1,3-Diaminoacetone dihydrochloride monohydrate (5.00 g, 27.9 mmol) was dissolved in refluxing methanol and o-ethylhydroxylamine hydrochloride (5.44 g, 55.8 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallisation from methanol/ethyl acetate afforded 2.30 g (48%) light-brown material. Mp. 163.8 °C. Example 3 1.6-Dihvdro-5(4H)-pvrimidinone O-(2-propvnyl)oxime monohvdrochloride 1,3-diaminoacetone dihydrochloride monohydrate (1.10 g, 6.14 mmol) was dissolved in refluxing methanol and 0-(2-propynyl)hydroxy1amine hydrochloride (0.730 g, 6.75 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved •• in methanol and an excess of trimethylorthoformate was added to the reaction mixture and heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallisation from methanol/ethyl acetate afforded 410 mg (36%) of light-brown material. Mp. 205.0 °C. Example 4 1.6-Dlhvdro-5(4H)-pvrimidinone O-(1-methvlethvl)oxime monohvdrochloride I,3-Diaminoacetone dihydrochloride monohydrate (2.0 g, II.2 mmol) was dissolved in refluxing methanol and 0-(l-methylethyl)hydroxylamine hydrochloride (2.5 g, 22.4 9 24 7 0 3 7 mmol) was added. After refluxing for 48 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture whxih was heated to reflux. After 24 hours the solvent was removed in vacuo. Crystallisation from methanol/ethyl acetate afforded 1.00 g (47%) light-brown material. Mp. 170.0 °C. 10 Example 5 I.6-Dihvdro-5(4in -pyrimidinone O-(cyclopropvlmethvl)-oxime monohvdrochlori de 15 1,3-Diaminoacetone dihydrochloride monohydrate (2.00 g, II.2 mmol) was dissolved in refluxing methanol and 0-(cyclopropylmethyl)hydroxylamine hydrochloride (2.60 g, 21.1 mmol) was added. After refluxing for 96 hours the solvent was evaporated. The crude product was dissolved 20 in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 48 hours the solvent was removed in vacuo. Crystallisation from methanol/ethyl acetate afforded r 1.30 g (57%) of light-brown material. Mp. 158.0 "C. 25 Example 6 o 1.6-Dihvdro-5(4HH -pyrimidinone O-f2-propenvl^oxime 30 monohydrQchlprifle 1,3-Diaminoacetone dihydrochloride monohydrate (2.00 g, 11.2 mmol) was dissolved in refluxing methanol and 0-2-propenylhydroxylamine hydrochloride (2.40 g, 21.9 mmol) 35 was added. After refluxing for 96 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the 10 247037 reaction mixture which was heated to reflux. After 48 hours the solvent was removed in vacuo. Crystallisation from methanol/ethyl acetate afforded 1.20 g (57%) of white material. Mp. 164.5 "C. Example 7 l, 6-Pihyflrp-s (4H) -pyriroifli.n<?ne Q-f phenylmethyl) oxime monohydrochloride I,3-Diarainoacetone dihydrochloride monohydrate (2.00 g, II.2 mmol) was dissolved in refluxing methanol and 0-phenylmethylhydroxylamine hydrochloride (3.30 g, 20.5 mmol) was added. After refluxing for 20 hours the solvent was evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 48 hours the solvent was removed in vacuo. Crystallisation from methanol/ethyl acetate afforded 1.60 g (60%) of white material. Mp. 167.5 °C. Example 8 In a similar manner as described in examples 1-7 were prepared: 1,6-Dihydro-5(4H)-pyrimidinone O-(1,l-dimethylethy1) oxime monohydrochloride. M.p. 199 "c. l,6-Dihydro-4-methyl-5(4H)-pyrimidinone O-ethyloxime monohydrochloride. M.p. 153 *C. 1,6-Dihydro-5(4H)-pyrimidinone 0-[ (2-chlorophenyl) methyl]oxime monohydrochloride. M.p. 187 °C. 11 24 7037 10 l,6-Dihydro-5(4H)-pyrimidinone 0-[(2-fluorophenyl) methyl]oxime monohydrochloride. M.p. 176 °C. 1,6-Dihydro-5(4H)-pyrimidinone 0-[(2- trifluoromethylphenyl) methyl]oxime monohydrochloride. M.p. 176 "C. 1,6-Dihydro-5(4H)-pyrimidinone O-propyloxime monohydrochloride. M.p. 147 °C. 1,6-Dihydro-5(4H)-pyrimidinone 0-(1-methylpropyl)oxime monohydrochloride. M.p. 178 *C. 1,6-Dihydro~5(4H)-pyrimidinone 0-(3-phenyl-2-propynyl) 15 oxime monohydrochloride. M.p. 168 °C. 1,6-Dihydro-2-methyl-5(4H)-pyrimidinone O-(2-propenyl) oxime monohydrochloride. M.p. 135 °C. 20 1,6-Dihydro-5(4H)-pyrimidinone 0-(2-butynyl) oxime monohydrochloride. M. p. 176 *C. 25 / (E)l,6-Dihydro-5(4H)-pyrimidinone 0-(3-methyl-2-penten-4-ynyl) oxime monohydrochloride. M.p. 186 °C. l,6-Dihydro-5(4H)-pyrimidinone 0-(2-butenyl) oxime monohydrochloride. M.p.136 *C. 1,6-Dihydro-5(4H)-pyrimidinone O-(nona-2,5,8-triynyl) 30 oxime monohydrochloride. 1#6-Dihydro-5(4H)-pyrimidinone O-butyloxime monohydrochloride. M.p. 145 *C. 35 l#6-Dihydro-5(4H)-pyrimidinone 0-(3-hexynyl) oxime monohydrochloride. </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 12 24 7 0 3 7 1,6-Dihydro-5(4H)-pyrimidinone 0-(2-methoxy-2-oxoethyl)oxime monohydrochloride. M.p. 167 °C. l,6-Dihydro-5(4H)-pyrimidinone O-phenyloxime monohydrochloride 1,6-Dihydro-5(4H)-pyrimidinone O-(cyanomethyl)oxime monohydrochloride 10 l/6-Dihydro-5(4H)-pyrimidinone O-acetyloxime monohydrochloride 1,6-Dihydro-5(4H)-pyrimidinone O-carbamoyloxime monohydrochloride 15 Example 9 1.4.5.6-Tetrahvdro-N-methoxv-5-pyrimidinamine 20 dihydrochloride A solution of l,6-dihydro-5~(4H)-^pyrimidinone O-methyl-oxim monohydrochloride (2.8 g, 17.1 mmol) in dry ■ methanol was added dropwise to a stirred solution of 25 HCl/methanol (49 ml of a 3N solution) and trimethylamine borohydride (1.36 g, 18.7 mmol) at room temperature under a nitrogen atmosphere. After 1 hour the reaction product crystallised spontaneously. Recrystallisation from methanol/ethyl acetate gave a light-brown material 30 in 38% yield (1.30 g). Mp. 214.0 °C. Example 10 35 In a similar manner as described in example 9 was prepared 1,4,5,6-Tetrahydro-N-ethoxy-5-pyrimidinamine dihydrochloride. M.p. 178 °C. 13 247037 N.2L PATENT OFFICE WHAT WE CLAIM IS: 'A 27 JUN1895 received

1. A tetrahydropyrimidine derivative having formula I *4 ° N. X ■s" 5 I *6 wherein c *1 is hydrogen; r2 is hydrogen, a lower alkyl group, or lower acyl; or Rj and R2 represent together a bond; Rg is hydrogen, COR^ or a lower hydrocarbon group optionally substituted with halogen, CN or aryl; R^ is hydrogen, a lower alk(en)yl group, or aryl (as herein ' defined); R,. is hydrogen, amino, lower alkyl substituted amino, or a lower alkyl group; Rg is hydrogen or methyl, provided that when R^ and R2 together represent a bond and R3, R^ and R5 are hydrogen, Rg is methyl; and R^ is amino, lower alkyl substituted amino, or a lower alkyl group; or a pharmaceutically acceptable salt thereof.

2. The tetrahydropyrimidine derivative of claim 1, in which Rjl and R2 represent together a bond, and R3 is a (1-3 C) hydrocarbon group, or a pharmaceutically acceptable salt thereof.

3. The tetrahydropyrimidine derivative of claim 2, in which R3 is ethyl and R4, Rg, and r6 are hydrogen, or a pharmaceutically acceptable salt thereof.

4. The tetrahydropyrimidine derivative of claim 2, in which R3 is 2-propynyl and R4, R5, and R6 are hydrogen, or a pharmaceutically acceptable salt thereof. 14

5. 1,6-Dihydro-5(4H)-pyrimidinone 0-(2-methoxy-2-oxoethyl) oxime monohydrochloride. *47037 10 15 20

6. A process for the preparation of the tetrahydropyrimidine derivative of any one of claims 1-4, characterized in that the preparation is performed by methods known for the preparation of analogous compounds.

7. A pharmaceutical composition comprising the tetrahydropyrimidine derivative of any one of claims 1-4 in admixture with pharmaceutically acceptable auxiliaries.

8. The tetrahydropyrimidine derivative of any one of claims 1-4 for use in therapy.

9. The tetrahydropyrimidine derivative of any one of . claims 1-4 for use in treatment of Alzheimer's disease or other cognitive disorders.

10. A use of the tetrahydropyrimidine derivative of any one of claims 1-4 for the preparation of a medicament which can be used for the treatment of cognition disorders, and for the treatment of cholinergic deficiencies.

11. A tetrahydropyrimidine derivative of any one of claims .1-5, substantially as herein described.

12. A tetrahydropyrimidine derivative of claim 1, substantially as described with reference to any one of the Examples. AKZO N.V. By Their Attorneys BALDWIN SON & CAREY 27 JUfi 1995 received </div>